Nerve growth factor scales endocannabinoid signaling by regulating monoacylglycerol lipase turnover in developing cholinergic neurons

Erik Keimpema, Giuseppe Tortoriello, Alán Alpár, Simona Capsoni, Ivan Arisi, Daniela Calvigioni, Sherry Shu Jung Hu, Antonino Cattaneo, Patrick Doherty, Kenneth Mackie, Tibor Harkany

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

Abstract

Endocannabinoid, particularly 2-arachidonoyl glycerol (2-AG), signaling has recently emerged as a molecular determinant of neuronal migration and synapse formation during cortical development. However, the cell type specificity and molecular regulation of spatially and temporally confined morphogenic 2-AG signals remain unexplored. Here, we demonstrate that genetic and pharmacological manipulation of CB1 cannabinoid receptors permanently alters cholinergic projection neuron identity and hippocampal innervation. We show that nerve growth factor (NGF), implicated in the morphogenesis and survival of cholinergic projection neurons, dose-dependently and coordinately regulates the molecular machinery for 2-AG signaling via tropomyosine kinase A receptors in vitro. In doing so, NGF limits the sorting of monoacylglycerol lipase (MGL), rate limiting 2-AG bioavailability, to proximal neurites, allowing cell-autonomous 2-AG signaling at CB1 cannabinoid receptors to persist at atypical locations to induce superfluous neurite extension. We find that NGF controls MGL degradation in vitro and in vivo and identify the E3 ubiquitin ligase activity of breast cancer type 1 susceptibility protein (BRCA1) as a candidate facilitating MGL's elimination from motile neurite segments, including growth cones. BRCA1 inactivation by cisplatin or genetically can rescue and reposition MGL, arresting NGF-induced growth responses. These data indicate that NGF can orchestrate endocannabinoid signaling to promote cholinergic differentiation and implicate BRCA1 in determining neuronal morphology.

Original languageEnglish
Pages (from-to)1935-1940
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number5
DOIs
Publication statusPublished - 2013 Jan 29

All Science Journal Classification (ASJC) codes

  • General

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